The importance of properly selected population controls for association studies of alcoholism cannot be overstated. Erroneous results are often due to the effects of population stratification and the consequent differences in allele frequencies between patient and control subjects when the two groups are not carefully matched. This project will develop an understanding of the population genetics, molecular evolution, and linkage disequilibrium across genes likely to be of particular importance in alcoholism: two Dopamine Receptor genes (DRD2 and DRD4) at different positions on chromosome 11. Existing polymorphisms will be physically mapped and new polymorphisms identified to provide broad coverage of the extent of each gene. Typing and haplotyping of these markers in populations from around the world will document variation and the extent of disequilibrium. Known functional variants will be placed into their evolutionary context by identifying the haplotypes in which they occur. The direction of mutation for each polymorphism will be determined by typing other higher primates (chimpanzees, gorillas, orangutans). The haplotype distribution in the different populations and knowledge of the direction of each mutation will give insight into the evolution of these metabolically important genes which will help in our understanding of the range (amount and frequency) of normal variation at these critical loci and in the proper design of association studies. Indications of which haplotypes may harbor cryptic but functionally relevant variation will follow whenever positive associations are found in some population(s).